Neurofibrillary Tangle Evolution in Mild Cognitive Impairment

The cerebral mantle receives a massive cholinergic innervation from AD-vulnerable neurons located within the nucleus basalis of Meynert (NBM; Ch4). The magnitude of Ch4 neuronal loss in AD is apparent in regional variations with the greatest loss in the posterior division (Ch4p), followed by the intermediate division (Ch4i), with the least affected being the anteromedial region (Ch4a). Tau protein oligomeric aggregates appear to be linked to toxicity. We suggest that Ch4 pathology occurs in a caudal to rostral progression, which is manifested in the sequential appearance of specific post-translational modifications related to toxic oligomer formation. Oligomeric structures show an unmasking of amino acids 2-18, the “Phosphatase Activation Domain” (PAD), which promotes activation of a signaling cascade that inhibits conventional kinesin-based anterograde fast axonal transport. Oligomers made in vitro, react to both our dimer-oligomer (TOC1) and PAD (TNT1) antibodies. Further, pseudophosphorylated S422 on tau (422S→E) in vitro results in a tau molecule that predominantly forms oligomers. We hypothesize that tau phosphorylated at 422 (pS422) will colocalize with both TOC1 and TNT1 in a caudal to rostral Ch4 subfield-dependent pattern. The mechanistic consequences of progressive tau pathology for Ch4 neuronal function will be assessed by combining laser capture microdissection with custom microarray profiling to delineate gene expression profiles of these tau immunolabeled cells. Furthermore, the mechanistic action of the oligomers will be tested in vitro using oligomers made with 422S→E tau, normal tau and D421 (caspase cleaved) tau. Taken together, these studies explore the molecular basis for selective cholinergic neuronal vulnerability during the progression of AD with single neuron resolution.